This patent application claims a benefit of priority from Korean Patent Application No. 2000/30895 filed Jun. 5, 2000, Korean Patent Application No. 2000/30896 filed Jun. 5, 2000, Korean Patent Application No. 2000/56035 filed Sep. 23, 2000 and Korean Patent Application No. 2001/11691 filed Mar. 7, 2001; through PCT Application Serial No. PCT/KR01/00821 filed May 18, 2001, the contents of each of which are incorporated herein by reference.
The present invention relates to novel oxazolidinone derivatives of formula 1 with antibacterial activity, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same. Also, the present invention is concerned with a method for the preparation thereof. 
Used as orally administrable antibacterial agents, oxazolidinone compounds are not products of fermentation, but artificially synthesized ones, and various structures of their derivatives are known. For instance, 3-phenyl-2-oxazolidinone derivatives having one or two substituents are stated in U.S. Pat. Nos. 4,948,801, 4,461,773, 4,340,606, 4,476,136, 4,250,318 and 4,128,654. 3-[(Monosubstituted)phenyl]-2-oxazolidinone derivatives of formula 2 are disclosed in EP 0312000, J. Med. Chem. 32, 1673(1989), and J. Med. Chem. 33, 2569 (1990), Tetrahedron, 45, 123(1989). 
Pharmcia and Upjohn developed oxazolidinone derivatives of formula 3 and 4 (WO 93/23384, WO 95/14684 and WO 95/07271). Having succeeded in gaining the approval of the FDA (Food and Drug Administration) of U.S.A., the oxazolidinone derivatives of formula 3 are going to come into the market. However, these conventional synthetic oxazolidinone compounds was found to suffer from the disadvantage of showing antibacterial activity against a narrow spectrum of bacteria, being toxic to humans, and being poor in therapeutic activity in vivo. 
WO 93/09103 discloses oxazolidinone derivatives of formula 1, substituted with heterocyclics such as thiazole, indole, oxazole, and quinole as well as pyridine, at position 4 of the phenyl ring. However, these oxazolidinone derivatives do not provide sufficient medicinal effects because the heterocyclics bear simple substituents such as alkyl or amino groups.
Leading to the present invention, the intensive and thorough research on oxazolidinone derivatives, conducted by the present inventors aiming to overcome the above problems encountered in prior arts, resulted in the finding that oxazolidinone derivatives substituted with pyridine or pyrimidine derivatives at the 4 position of the phenyl ring have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo.
Therefore, it is an object of the present invention to provide oxazolidinone derivatives of formula 1, which potent in inhibitory activity against a broad spectrum of bacteria, and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a process for preparing such an oxazolidinone derivative of formula 1, or its pharmaceutically acceptable salt.
It is a further object of the present invention to provide a pharmaceutical composition comprising such an oxazolidinone derivative of formula 1, or its pharmaceutically acceptable salt as a therapeutically effective ingredient.
In accordance with an aspect of the present invention, there is provided an oxazolidinone derivative of formula 1: 
wherein,
R1 is H, F, Cl or CF3;
R2 is 
where R3 is
1) H,
2) C1-C4 alkoxy, or piperazinyl optionally substituted with R5,
where R5 is:
(a) H;
(b) Triphenylmethyl;
(c) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of benzyloxyacetyl, acetoxyacetyl, hydroxy acetyl, C1-C3 alkylaminoacetoxyacetyl, acetyl substituted with halogen, morpholi-4-nylacetyl, imidazol-1-ylcarbonyloxy acetyl, C1-C3 alkoxycarbonylmethylaminoacetyl, C1-C3 alkoxyacetyl, t-butyl acetyl, phenyl acetyl optionally substituted with C1-C3 alkoxy, and C1-C3 alkoxyoxoacetyl;
(d) substituted or unsubstituted benzoyl, provided that the substituted benzoyl is selected from the group consisting of C1-C4 selected from the group consisting of C1-C4 alkoxybenzoyl, trihalomethylbenzoyl and nitrobenzoyl;
(e) substituted or unsubstituted carbonyl, provided that the substituted carbonyl is selected from the group consisting of C1-C4 haloalkylcarbonyl, phenoxycarbony, and benzyloxycarbonyl;
(f) C1-C3 alkoxyphenyl of;
(g) acryloyl optionally substituted with C1-C3 alkyl;
(h) nicotinoyl;
(i) pivaloyl;
(j) crotonyl, or
(k) n-valeryl,
R4 is: H; azido; xe2x80x94(Cxe2x95x90O)1xe2x80x94R6; xe2x80x94NR7R8; xe2x80x94(CH2)mxe2x80x94R9; or xe2x80x94OR10,
wherein R6 is: H; C1-C3 alkoxy; amino; C1-C3 alkylamino; or C1-C3 hydroxyalkylamino,
l is an integer of 1 or 2,
R7 and R8, which may be the same or different, represent,
(a) H;
(b) C1-C4 alkyl optionally substituted with one or more phenyl groups, or C1-C4 alkenyl substituted with C1-C3 alkylamino;
(c) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of acetoxyacetyl, hydroxyacetyl, C1-C3 alkylaminoacetoxyacetyl, C1-C3 alkoxyacetyl, aminoacetyl, azidoacetyl, acetylaminoacetyl, C1-C3 alkylaminoacetyl, aminopropionyl, and hydroxylpropionyl; or
(d) nicotinoyl,
R9 is: H; azido; hydroxy; C1-C3 alkylaminoacetoxy; acetylthio, mercapto, cyano, a halogen atom, or a 5- or 6-membered heterocycle,
m is an integer of 1-4,
R10 is: H; C1-C3 alkyl; acetyl; alkoxyalkyl; methanesulfonyl; or Heterocylic rings selected from the group consisting of
a) 5- or 6-membered heteroring containing one or more N or O as ring members, preferably represented by the following formula: 
b) a 5-membered heterocyclic ring containing at least one nitrogen or oxygen atom or both of them, as ring members, in which any one carbon atom is saturated with two hydrogen atoms or forms a double bond with oxygen (ketone), nitrogen (imino) or sulfur (thioketone), preferably of the following formula: 
xe2x80x83wherein A, B, and D, which may be the same or different, each represents a carbon, an oxygen or a nitrogen atom, and E represents two hydrogen atoms, an oxygen, a sulfur, or a nitrogen atom, and more preferably of the following formula: 
c) 5- or 6-membered hetero aromatic ring containing C, N, O or S as ring members and preferably one or two N or O, or at least one nitrogen and at least one oxygen atom together, as ring members of the following formula: 
wherein R11 and R12, which are the same or different, each represents:
(i) H, F, Cl, Br or I;
(ii) C1-C4 alkyl substituted optionally with at least one substituent, provided that the substituted alkyl is selected from the group consisting of hydroxyalkyl, alkoxycarbonylalkyl, trihaloalkyl, acetoxyalkyl, alkylaminoalkyl, alkoxyalkyl, and methanesulfonyloxyalkyl;
(iii) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of acetoxyacetyl, hydroxyacetyl, C1-C3 alkylamino acetoxyacetyl, C1-C3 alkoxyacetyl, aminoacetyl, azidoacetyl, acetylaminoacetyl, C1-C3 alkylaminoacetyl, aminopropionyl, and hydroxypropionyl;
(iv) azido, hydroxy, mercapto, cyano, ketone, or amino;
(v) substituted or unsubstituted imino, provided that the substituted imino is selected from the group consisting of hydroxyimino, alkylimino, alkoxyimino or methanesulfonyloxyimino;
(vi) hydrozino optionally substituted with alkoxycarbonyl;
(vii) xe2x80x94OR13, where R13 is H, C1-C3 alkyl, acetyl, alkoxyalkyl, hydroxyacetyl or methanesulfonyl;
(viii) xe2x80x94NR14R15, wherein R14 and R15 represent independently H, C1-C3 alkyl, acetyl, alkoxylalkyl, hydroxyacetyl or methansulfonyl;
(ix) xe2x80x94(Cxe2x95x90O)xe2x80x94(R16)nxe2x80x94,
wherein R16 is:
xe2x80x831) C1-C6 alkyl, or alkenyl optionally substituted with C1-C3 alkyl;
xe2x80x832) alkoxycarbonyl;
xe2x80x833) acetoxymethyl, benzyloxymethyl, hydroxymethyl, C1-C3 alkylacetoxymethyl, halomethyl, C1-C3 alkoxymethyl, morpholinylmethyl, C1-C3 alkoxycarbonylmethyl aminomethyl, C1-C3 methanesulfonyloxymethyl, alkoxyoxomethyl, C1-C3 nicotinoyloxymethyl, alkoxyphenylmethyl, benzyl, or trihalomethyl;
xe2x80x834) C1-C3 alkoxy, phenyloxy, allyloxy, C1-C3 haloalkyloxy, benzyloxy optionally substituted with nitoro, or 9-fluorenylmethyloxy;
xe2x80x835) Nicotinoylmethyl; or
xe2x80x836) a 5- or 6-membered heterocyclic ring
Preferable, concrete examples of the compounds of formula 1 include:
1) (S)-[N-3-(4-pyrimidin-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 1)
2) (S)-[N-3-(4-(2-methoxypyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 2)
3) (S)-[N-3-(4-(2-aminopyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 3)
4) (S)-[N-3-(4-(2-(4-triphenylmethylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 4)
5) (S)-[N-3-(4-(2-piperazin-1-ylpyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 5)
6) (S)-[N-3-(4-(2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 6)
7) (S)-[N-3-(4-(2-(4-benzyloxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 7)
8) (S)-[N-3-(4-(2-(4-acetoxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 8)
9) (S)-[N-3-(4-(2-(4-hydroxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 9)
10) (S)-[N-3-(4-(2-(4-dimethylaminoacetoxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 10)
11) (S)-[N-3-(4-(2-(4-bromoacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 11)
12) (S)-[N-3-(4-(2-(4-morpholin-4-ylacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 12)
13) (S)-[N-3-(4-(2-(4-imidazol-1-ylcarbonyloxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 13)
14) (S)-[N-3-(4-(2-(4-chloroacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 14)
15) (S)-[N-3-(4-(2-(4-methoxycarbonylmethylaminoacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidiyl]methyl acetamide (compound of Example 15)
16) (S)-[N-3-(4-(2-(4-(4-methoxyphenylpiperazin-4-yl)acetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 16)
17) (S)-[N-3-(4-(2-(4-methoxyacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 17)
18) (S)-[N-3-(4-(2-(4-acryloylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 18)
19) (S)-[N-3-(4-(2-(4-ethoxyoxoacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 19)
20) (S)-[N-3-(4-(2-(4-nicotinoylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 20)
21) (S)-[N-3-(4-(2-(4-pivaloylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 21)
22) (S)-[N-3-(4-(2-(4-t-butylacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 22).
23) (S)-[N-3-(4-(2-(4-(2,5-dimethoxyphenyl)acetylpiperazine-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 23)
24) (S)-[N-3-(4-(2-(4-(3,3-dimethylacryloyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 24)
25) (S)-[N-3-(4-(2-(4-(2,6-dimethoxybenzoyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 25)
26) (S)-[N-3-(4-(2-(4-(2-trifluoromethylbenzoyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example-26)
27) (S)-[N-3-(4-(2-(4-(4-trifluoromethylbenzoyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 27)
28) (S)-[N-3-(4-(2-(4-phenylacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 28)
29) (S)-[N-3-(4-(2-(4-(3,5-dinitrobenzoyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 29)
30) (S)-[N-3-(4-(2-(4-crotonylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 30)
31) (S)-[N-3-(4-(2-(4-trichloroacetylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 31)
32) (S)-[N-3-(4-(2-(4-n-valerylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 32)
33) (S)-[N-3-(4-(2-(4-(1-bromoethylcarbonyl)piperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 33).
34) (S)-[N-3-(4-(2-(4-phenoxycarbonylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 34)
35) (S)-[N-3-(4-(2-(4-benzyloxycarbonylpiperazin-1-yl)pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 35)
36) (S)-[N-3-(4-pyridin-2-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 36)
37) (S)-[N-3-(4-(2-aminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 37)
38) (S)-[N-3-(4-(3-methoxycarbonylpyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 38)
39) (S)-[N-3-(4-(2-acetylaminopyridin-5-yl)-3-fluorophenyl)-?-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 39)
40) (S)-[N-3-(4-(2-acetoxyacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 40)
41) (S)-[N-3-(4-(2-hydroxyacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 41)
42) (S)-[N-3-(4-(2-imidazol-1-yl-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 42)
43) (S)-[N-3-(4-(2-morpholin-4-yl-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 43)
44) (S)-[N-3-(4-(2-triphenylmethylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 44)
45) (S)-[N-3-(4-(2-methoxypyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 45)
46) (S)-[N-3-(4-(2-methoxyacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 46)
47) (S)-[N-3-(4-(2-(4-triphenylmethylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 47)
48) (S)-[N-3-(4-(2-triphenylmethylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 48)
49) (S)-[N-3-(4-(2-azidopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 49)
50) (S)-[N-3-(4-(2-hydroxymethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 50)
51) (S)-[N-3-(4-(2-methoxycarbonylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 51)
52) (S)-[N-3-(4-(2-dimethylaminocarbonylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 52)
53) (S)-[N-3-(4-(2-hydroxypyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 53)
54) (S)-[N-3-(4-(N-2-dimethylaminoacetoxyacetylaminopyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 54)
55) (S)-[N-3-(4-(2-methylaminopyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 55)
56) (S)-[N-3-(4-(2-dimethylaminopyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 56)
57) (S)-[N-3-(4-(2-hydroxyacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide
65) (S)-[N-3-(4-(2-N,N-di(2-hydroxyethyl)aminocarbonylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 65)
66) (S)-[N-3-(4-(2-piperazin-1-ylpyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 66)
67) (S)-[N-3-(4-(2-(4-acetoxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 67)
68) (S)-[N-3-(4-(2-(4-benzyloxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 68)
69) (S)-[N-3-(4-(2-(4-hydroxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 69)
70) (S)-[N-3-(4-(2-(4-dimethylaminoacetoxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 70)
71) (S)-[N-3-(4-(2-(4-chloroacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 71)
65) (S)-[N-3-(4-(2-N,N-di(2-hydroxyethyl)aminocarbonylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 65)
66) (S)-[N-3-(4-(2-piperazin-1-ylpyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 66)
67) (S)-[N-3-(4-(2-(4-acetoxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 67)
68) (S)-[N-3-(4-(2-(4-benzyloxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 68)
69) (S)-[N-3-(4-(2-(4-hydroxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 69)
70) (S)-[N-3-(4-(2-(4-dimethylaminoacetoxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 70)
71) (S)-[N-3-(4-(2-(4-chloroacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 71)
72) (S)-[N-3-(4-(2-(4-acetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 72)
73) (S)-[N-3-(4-(2-(4-methoxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 73)
74) (S)-[N-3-(4-(2-(4-morpholinylacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 74)
75) (S)-[N-3-(4-(2-(4-methoxycarbonylmethylaminoacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 75)
76) (S)-[N-3-(4-(2-(4-ethoxycarbonylpiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 76)
77) (S)-[N-3-(4-(2-azidomethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 77)
78) (S)-[N-3-(4-(2-imidazol-1-yl)methylpyridin-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 78)
79) (S)-[N-3-(4-(2-morpholin-4-yl)methylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 79)
80) (S)-[N-3-(4-(2-acetylthiomethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 80)
81) (S)-[N-3-(4-(2-mercaptomethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 81)
82) (S)-[N-3-(4-(2-(4-methanesulfonyloxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 82)
83) (S)-[N-3-(4-(2-(4-acryloylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 83)
84) (S)-[N-3-(4-(2-(4-ethoxyoxoacetylpiperazin-1-yl)pyridin-1-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 84)
85) (S)-[N-3-(4-(2-(4-nicotinoylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 85)
86) (S)-[N-3-(4-(2-(4-pivaloylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 86)
87) (S)-[N-3-(4-(2-(4-tetrabutylacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 87)
88) (S)-[N-3-(4-(2-(4-nicotinoyloxyacetylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 88)
89) (S)-[N-3-(4-(2-(4-(2,5-dimethoxyphenylacetyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 89)
90) (S)-[N-3-(4-(2-(4-(3,3-dimethylacryloyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 90)
91) (S)-[N-3-(4-(2-(4-(2,6-dimethoxybenzoyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 91)
92) (S)-[N-3-(4-(2-(4-(2-trifluoromethyl)benzoyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 92)
93) (S)-[N-3-(4-(2-(4-(4-trifluoromethyl)benzoyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 93)
94) (S)-[N-3-(4-(2-(4-benzylcarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 94)
95) (S)-[N-3-(4-(2-(4-crotonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 95)
96) (S)-[N-3-(4-(2-(4-trifluoromethylcarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 96)
97) (S)-[N-3-(4-(2-(4-n-valerylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 97)
98) (S)-[N-3-(4-(2-(4-phenyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 98)
99) (S)-[N-3-(4-(2-(4-allyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 99)
100) (S)-[N-3-(4-(2-(4-(1-chloroethy)oxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 100)
101) (S)-[N-3-(4-(2-(4-(4-nitrobenzyl)oxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 101)
102) (S)-[N-3-(4-(2-(4-benzyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 102)
103) (S)-[N-3-(4-(2-(4-(9-fluorenylmethyloxycarbonyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazoldinyl]methyl acetamide (compound of Example 103)
104) (S)-[N-3-(4-(2-(4-(2-pyrimidinyl)piperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 104)
105) (S)-[N-3-(4-(2-(4-methoxycarbonylmethylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 105)
106) (S)-[N-3-(4-(2-fluoromethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 106)
107) (S)-[N-3-(4-(2-cyanomethylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 107)
108) (S)-[N-3-(4-(2-methylpyridin-4-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 108)
109) (S)-[N-3-(4-(2-(4-(2-hydroxy)ethylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 109)
110) (S)-[N-3-(4-(2-(4-(2-acetoxy)ethylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 110)
111) (S)-[N-3-(4-(2-(4-methoxycarbonylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methylacetamide (compound of Example 111)
112) (S)-[N-3-(4-(2-(4-(2-methanesulfonyloxy)ethylpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 112)
113) (S)-[N-3-(4-(2-(4-hydroxymethyl)imidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 113)
114) (S)-[N-3-(4-(2-aminoacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 114)
115) (S)-[N-3-(4-(2-(4-cyanopiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 115)
116) (S)-[N-3-(4-(2-(4-carboxamideoximpiperazin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 116)
117) (S)-[N-3-(4-(2-(4-oxopiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 117)
118) (S)-[N-3-(4-(2-azidoacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 118)
119) (S)-[N-3-(4-(2-(1,2,3,4,6,7-hexahydro-5-oxo-1,4-diazepan-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 119)
120) (S)-[N-3-(4-(2-N-(dimethylaminomethylene)aminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 120)
121) (S)-[N-3-(4-(2-(4-hydroxyiminopiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 121)
122) (s)-[N-3-(4-(2-(4-methanesulfonyloxyiminopiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 122)
123) (S)-[N-3-(4-(2-(4-methyliminopiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 123)
124) (S)-[N-3-(4-(2-(4-methoxycarbonylhydrazino piperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 124)
125) (S)-[N-3-(4-(2-N-(L-alanyl)aminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 125)
126) (S)-[N-3-(4-(2-acetylaminoacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 126)
127) (S)-[N-3-(4-(2-dimethylaminoacetylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 127)
128) (S)-[N-3-(4-(2-nicotinoylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 128)
129) (S)-[N-3-(4-(2-(1,2,4-triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 129)
130) (S)-[N-3-(4-(2-(4-hydroxypiperidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 130)
131) (S)-[N-3-(4-(2-N,N-(hydroxyacetyl)methylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 131)
132) (S)-[N-3-(4-(2-(4-methylimidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 132)
133) (S)-[N-3-(4-(2-(2-hydroxypropionyl)aminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 133)
134) (S)-[N-3-(4-(2-(3-amino-1,2,4-triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 134)
135) (S)-[N-3-(4-(2-(4-ethoxycarbonylimidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 135)
136) (S)-(N-3-(4-(2-(1-tetrazolyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide (compound of Example 136)
137) (S)-[N-3-(4-(2-(5-methyl-(1,3,4)-oxadiazol-2-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 137)
138) (S)-[N-3-(4-(2-(5-methyl-(1,2,4)-oxadiazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 138)
139) (S)-[N-3-(4-(2-(1-methyl-5-tetrazolyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 139)
140) (S)-[N-3-(4-(2-(2-methyl-5-tetrazolyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 140)
141) (S)-[N-3-(4-(2-(4-ethoxycarbonyl-(1,2,3)-triazol-1-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 141)
142) (S)-[N-3-(4-(2-(3-pyrrolynyl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 142)
143) (S)-[N-3-(4-(2-(2-oxo-(1,3)-oxazolidin-3-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 143)
144) (S)-[N-3-(4-(2-((1,3)-oxazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 144)
145) (S)-[N-3-(4-(2-((1,2,4)-oxadiazol-3-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 145)
146) (S)-[N-3-(4-(2-((1,2,3)-triazol-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 146)
147) (S)-[N-3-(4-(2-(3-methyl-2-oxo-2,3-dihydro-(1,3,4)-triazol-1-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 147)
148) (S)-[N-3-(4-(2-(2-oxo-(1,3)-imidazolidin-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 148)
149) (S)-[N-3-(4-(2-(4-hydroxy-piperidin-1-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 149)
150) (S)-[N-3-(4-(2-(2-oxo-(2,3)-dihydro-(1,3,4)-triazol-1-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 150)
151) (S)-[N-3-(4-(2-(5-hydroxymethyl-(1,2,4)-oxadiazol-3-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 151)
152) (S)-[N-3-(4-(2-(5-tetrazolyl)-5-pyridinyl)-3-fluoro phenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 152)
153) (S)-[N-3-(4-(2-(5-methoxymethyl-(1,2,4)-oxadiazol-3-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 153)
154) (S)-[N-3-(4-(2-(5-trichloromethyl-(1,2,4)-oxadiazol-3-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 154)
155) (S)-[N-3-(4-(2-(5-dimethylamino-(1,2,4)-oxadiazol-3-yl)-5-pyridinyl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 155)
156) (S)-[N-3-(4-(2-(5-amino-(1,2,4)-oxadiazol-3-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 156)
157) (S)-[N-3-(4-(2-(4-acetylamino-1-piperidinyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 157)
158) (S)-[N-3-(4-(2-(4-acetyloxymethylcarbonylamino-piperidin-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 158)
159) (S)-[N-3-(4-(2-(4-hydroxymethylcarbonylamino-piperidin-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 159)
160) (S)-[N-3-(4-(2-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 160).
More preferable examples of the compounds of formula 1 include;
1) (S)-[N-3-(4-(2-(1,2,4-triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 129),
2) (S)-[N-3-(4-(2-(5-methyl-(1,3,4)-oxadiazol-2-yl)-pyridin-5-yl)3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 137),
3) (S)-[N-3-(4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 138),
4) (S)-[N-3-(4-(2-(1-methyl-5-tetrazolyl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 139), and
5) (S)-[N-3-(4-(2-oxo-(1,3)-oxazolidin-3-yl)-pyridin-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl acetamide (compound of Example 143).
As for the pharmaceutically acceptable salt, it is preferably an acid addition salt prepared by use of a pharmaceutically acceptable free acid. Whether it is inorganic or organic, a free acid can be used if it is pharmaceutically acceptable. Examples of the inorganic free acid include hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid. Available organic free acids are exemplified by citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, galuturonic acid, embonic acid, glutamic acid, and aspartic acid.
In addition, the pharmaceutically acceptable salt of the compound of formula 1 can be prepared using a base. Available is pharmaceutically acceptable metals, especially alkaline metal. Examples of useful metal include sodium and potassium.
In accordance with another aspect of the present invention, there is provided a method for preparing an oxazolidinone derivative of formula 1. As se en in the following Scheme 1, the preparation of the oxazolidinone derivative is achieved by reacting a triyethylstanyl oxazolidinone derivative 2 with a pyridine derivative 3 in the presence of a palladium catalyst. 
(wherein R1, R2 and X are each as defined above).
A detailed reaction route for the preparation of the oxazolidinone derivative of the present invention is illustrated in the following Scheme 2. As shown, the oxazolidinone derivative is prepared by:
a) aminating a hydroxymethyloxazolidinone derivative 4 at its hydroxy group to give an amine compound 5 (step 1),
b) acetylating the amine compound 5 by use of acetic anhydride to produce an acetyl compound 6 (step 2),
c) halogenating the acetyl compound 6 at its phenyl ring to produce a halogen compound 7 (step 3);
d) stannylating the halogen compound 7 in the presence of a palladium catalyst to give a trimethylstannyl oxazolidinone derivative 2 (step 4), and
e) substituting the trimetyistannyl group of the oxazolidinone derivative 2 with a pyridine or pyrimidine moiety in the presence of a palladium catalyst to yield a compound 1 (step 5). 
wherein R1 and R2 are as defined above, and X is a halogen atom.
Below, a detail description will be stepwise given of the method for preparing oxazolidinone derivatives of the present invention
The hydroxymethyl oxazolidinone derivative of formula 4, used as the starting material in Scheme 4, can be readily synthesized by well-known processes. For example, a benzyloxycarbonyl group is introduced into the amine group of aniline and then reacted with glycidylbutyrate in the presence of a strong base to obtain the starting material. Examples of the strong base suitable for use in this synthesis include n-butyl lithium, sec-butyl lithium and tert-butyl lithium with preference for n-butyl lithium. The synthesis is preferably carried out at xe2x88x9278xc2x0 C.
In the step 1, the hydroxy group of the hydroxymethyloxazolidinone derivative 4 is converted into an amine group. In this regard, a leaving group is first attached to the hydroxy group for the introduction of an azide group which is then reduced into an amine group.
Suitable as the leaving group are methane sulfonyl, para-toluene sulfonyl, and halogen. Preferably, the attachment of the leaving group is conducted at 0xc2x0 C.
Because azide is a good nucleophile, the leaving group, such as methane sulfonyl, para-toluene sulfonyl or halogen, can be readily substituted by azide through nucleophilic displacement. For this reaction, sodium azide is used in an amount of about 1 to 3 equivalents relative to the methyloxazolidinone derivative reactant. The nuclegophilic displacement is preferably carried out 80 to 110xc2x0 C. for 1 to 2 hours in a solvent, which is exemplified by dimethylformamide, dimethylsulfoxide and 1,4-dioxane.
Next, reduction of the resulting azide provides the primary amine of formula 5. This reduction is achieved by catalytic hydrogenation or by use of triphenyl phosphine. As for the catalytic hydrogenation, it is preferably carried out at room temperature under a hydrogen atmosphere using palladium in a solvent selected from the group consisting of tetrahydrofuran, methanol and mixtures thereof. When using triphenyl phosphine, the azide compound is refluxed in a tetrahydrofuran solution added with a small amount of water for 2 hours to produce the primary amine.
In the step 2, the amine compound of the formula 5, obtained in the step 1, is reacted with acetic anhydride in the presence of a base to give the corresponding compound of formula 6. Suitable base for use in this acetylation are triethyl amine, pyridine, and diisopropylethyl amine.
In the step 3, the compound of formula 6 is halogenated on position 4 of its phenyl ring to produce the corresponding compound of formula 7.
Preferable halide with which the phenyl ring is substituted is iodide. The iodination is preferably conducted by reacting the compound of formula 6 with iodine monochloride (ICl) alone, or iodine in the presence of silver trifluoroacetate (CF3COOAg) at room temperature.
In the step 4, the halide group on position 4 of the phenyl ring is displaced with trimethyl stannyl by reaction with hexametylditin in the presence of a palladium catalyst to give the trimethylstannyl oxazolidinone derivative of formula 2. Dichlorobistriphenylphosphine palladium (II), or tetrakistriphenylphosphine palladium (0) is useful as the palladium catalyst.
This displacement is preferably carried out at 90 to 120xc2x0 C. in a solvent, such as 1,4-dioxane, dimethylformamide, or tetrahydrofuran.
In the step 5, the trimethylstannyl oxazolidinone derivative of formula 2 is reacted with the pyridine or pyrimidine derivative of formula 3 in the presence of a palladium (0) or a palladium (II) catalyst to prepare the oxazolidinone compound of the present invention.
Preferably, this reaction is conducted at 60 to 150xc2x0 C. for about 30 min to 12 hours. As a solvent for the reaction, dimethylformamide, 1,4-dioxane, and tetrahydrofuran may be used alone or in combination.
For use in the present invention, the pyridine halide of formula 3 can be prepared from, for example, dibromopyridine and pyridine, as illustrated in Scheme 3. Such preparation is reported in the literature (J. Medicinal Chem. V41, 2399(1998), Chem. Pharm. Bull, 314(1996), J. Med. Chem. 957(2000), J. Med. Chem. 1230(2000), J. Med. Chem. 1086(1991), J. Med. Chem. 2837(1997), J. Med. Chem. 2019(1998)) 
Wherein, R2 and X are as defined above.
When R2 is piperazinylpyrimidine, the synthesis of the compound of formula 1 progress by way of the intermediates of Scheme 4
wherein, R1 and R3 are each as defined above, and X is a halogen atom.
As illustrated in Scheme 4, the trimetylstannly group of the compound of formula 2 is displaced with triphenylmethyl-protected piperazine pyrimidine, followed by the removal of the protecting group by use of a hydrochloric acid solution. The resulting deprotected compound of formula 11 is substituted on the amine group of the piperidine moiety to synthesize the compound of formula 12.
When R2 is pyridine, the synthesis of the compound of formula 1 progress by way of the intermediates of Scheme 5
Wherein R1, R2, R6 and X are each as defined above, and L is a typical leaving group and preferably halogen or methylcarbonyl oxy group.
As illustrated in Scheme 5, the trimethylstannyl, oxazolidinone derivative of formula 2 is reacted with a cyanopyridine derivative to synthesize an intermediate of formula 13, whose cyano group is then subjected to imination using hydroxylamine to form the corresponding compound of formula 14. It is cyclized to the desired compound as a result of reaction with a carboxylic acid derivative.
As for the synthesis of the intermediate of formula 13, it is performed by refluxing the reactants at 100 to 120xc2x0 C. for 4 to 10 hours in an organic solvent, such as N-methylpyrrolidine or tetrahydrofuran.
In the presence of sodium hydrogen carbonate and hydroxylamine hydrochloride, the compound of formula 13 is iminated at a reflux temperature for 2 to 5 hours. Alcohols can be used as solvents with preference for ethanol, methanol or isopropanol.
Reaction of the compound of formula 14 with an activated carboxylic acid derivative provides the oxazolidinone derivative of formula 1. The activated carboxylic acid derivative is acyl chloride in which R6 is substituted, or acetic anhydride. The cyclization is conducted at a reflux temperature for 4 to 8 hours in a solvent such as pyridine, tetrahydrofuran or acetone.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of formula 1 as an effective ingredient conferring antibacterial activity.
For formulating a pharmaceutical composition, at least one species of the compound of formula 1 is admixed with at least one pharmaceutically acceptable expedient, which is nontoxic to humans and inactive.
Administrable via oral or parenteral routes, the compounds of formula 1 may be used with ordinary medicine forms.
That is, the compounds of formula 1 can be formulated into various dosage forms for oral or parenteral administration. For formulation, pharmaceutically acceptable diluents, expedients and/or carriers may be used, including fillers, thickeners, binders, wetting agents, disintegrants, surfactants, etc. Solid dosage forms for oral administration are exemplified by tablets, pills, powders, granules, and capsules. These solid forms are prepared by admixing at least one compound of formula 1 with at least one expedient, such as starch, calcium carbonate, sucrose, lactose, gelatine, etc. In addition to expedients, a lubricant such as magnesium styrate may be added.
Exemplified by suspensions, internal solutions, emulsions, syrups, etc., liquid dosage forms for oral administration may comprise simple diluents, such as water and liquid paraffin, as well as wetting agents, sweeteners, aromatics, and/or perspectives.
Dosage forms for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried agents, suppositories, etc. For formulation of non-aqueous solvents and suspensions, vegetable oils, such as propylene glycol and polyethylene glycol, or injectable esters such as ethyl oleate, may be used. As bases for suppositories, Witepsol, macrogol, Tween 61, cocoa oil, laurinic acid, and glycerogelatine are useful.
In general, the compound of formula 1 may be administered in a total dose of 1.2 g to adults in 2 or 3 installments a day. However, the dose may vary depending on the conditions of the subject, including, for example, physical constitutions and weights of patients, kinds and severity of diseases, administration routes and intervals, etc.
It is found that not only does the compound of formula 1 show inhibitory activity against a broad spectrum of bacteria, but its antibacterial activity is excellent in vivo. For example, the compound of the present invention can exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium. 